Process for the preparation of phenothiazine granules having improved properties

ABSTRACT

A process for the preparation of phenothiazine granules having a narrow particle size distribution, phenothiazine having a purity of at least 98% in liquid form being forced through a means provided with holes and a frequency being applied to the liquid phenothiazine and the liquid phenothiazine emerging through the holes entering a cooling medium having a temperature in the range of from −196 to =120° C. so that the liquid phenothiazine drops thus produced are brought to a temperature below the melting point and said drops are, if required, further solidified in a downstream cooling zone.

This application is a continuation of application Ser. No. 10/312,019filed on Aug. 11, 2003 (now U.S. Pat. No. 6,983,612 issued Jan. 10,2006), which was a national stage filing under 35 U.S.C. 371 ofPCT/EP01/02681 filed on Mar. 9, 2001, which claimed priority on GermanApplication No. 100 32 137.2 filed on Jul. 1, 2000.

A process for the preparation of phenothiazine granules having a narrowparticle size distribution, phenothiazine having a purity of at least98% in liquid form being forced through a means provided with holes anda frequency being applied to the liquid phenothiazine and the liquidphenothiazine emerging through the holes entering a cooling mediumhaving a temperature in the range of from −196 to =120° C. so that theliquid phenothiazine drops thus produced are brought to a temperaturebelow the melting point and said drops are, if required, furthersolidified in a downstream cooling zone.

BACKGROUND

The present invention relates to a process for the preparation ofphenothiazine granules having improved solubility and handlingproperties.

Phenothiazine (2,3,5,6-dibenzo-1,4-triazine, CAS No. 92-84-2) is astarting material for thiazine dyes and sulfur dyes, an intermediate forthe preparation of drugs and is furthermore used as an antioxidant forlubricating oils and engine oils, as anthelmintics (in the veterinarymedicine sector), as an agent against fruit, vegetable, cereal andcotton pests and, in the largest amount, as a polymerization inhibitorfor ethylenically unsaturated carboxylic acids (Ullmann, XX Edition,Vol. 18, page 259 et seq.; Rompps Chemie-Lexikon, 8th Edition, page3133).

Phenothiazine is produced on an industrial scale by reactingdiphenylamine and sulfur in the presence of catalysts. Hydrogen sulfideformed thereby is bound with sodium hydroxide solution to give sodiumhydrosulfide. The crude phenothiazine formed is then purified bysuitable purification methods, for example by distillation under reducedpressure or steam distillation. The melting point of pure phenothiazineis 185.5-185.9° C. and the boiling point at atmospheric pressure is 371°C.

SUMMARY OF INVENTION

Depending on the intended use, after preparation and purification,phenothiazine subjected to a final manufacturing step, i.e. is broughtinto suitable solid forms. For use as anthelmintics, phenothiazine isused, for example, in a particle size of less than 30 pm, preferablyless than 20 pm (AU-B-254 331). This patent describes the preparation ofphenothiazine having a specific surface area of 25.000 cms²/g byvaporizing crude or commercial phenothiazine and then condensing it in agas stream by thorough mixing of the gas streams, phenothiazine having apurity of >95% and in the form of crystalline particles with a specificsurface area of at least 25.000 cms²/g being said to be obtained. Owingto the economic advantages, AU-B-254 331 furthermore mentions the use ofa fluidized bed as a preferred method for the preparation ofthe-phenothiazine particles described. Furthermore, it is stated therethat the fluidized bed consists of porous aluminum silicates or porousforms of alkali metal and alkaline earth metal carbonates or othersalts, to which the phenothiazine is applied by the fluidized-bedprocess.

U.S. Pat. No. 3,235,453 describes further methods for the preparation ofphenothiazine particles. Specifically, the comminution of precomminutedphenothiazine by means of a hammer mill and the use of micropulverizers,ball mills, air jet mills or wet milling are mentioned.

With the object of preparing phenothiazine having a very small particlesize, U.S. Pat. No. 3,235,453 describes the preparation of an improvedmixture, phenothiazine being dissolved in a solvent and brought intocontact with a solid and the solvent then being removed.

All stated methods have the object of preparing phenothiazine having avery small particle size (for use as anthelmintics) since the action ofcontact poisons is better the smaller the particle size.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution rate of phenothiazine in acrylic acid.

FIG. 2 shows the dissolution rate of phenothiazine in acrylic acid.

FIG. 3 shows the pantile size distribution of phenothiazine scales.

FIG. 4 shows the pantile size distribution of phenothiazine prills(granules 1).

FIG. 5 shows the pantile size distribution of phenothiazine (granules2).

DETAILED DESCRIPTION

For use as a polymerization inhibitor for ethylenically unsaturatedcarboxylic acids, phenothiazine is employed in solid form and is used,for example, in the distillation of acrylic acid in the productionprocess on an industrial scale. Phenothiazine remains substantially inthe residue of the distillation. Phenothiazine is such an effectiveinhibitor for acrylic acid that its use usually leads to problems in thepolymerization of acrylic acid, the main field of use. For this reasonand because of the dark color of phenothiazine, acrylic acid isgenerally inhibited using other inhibitors, e.g. hydroquinone monomethylether, a colorless compound (L. B. Levy, Inhibition of Acrylic AcidPolymerization by Phenothiazine and p-Methoxyphenol, Journal of PolymerScience, Polymer Chemistry Edition, Vol. 23, 1505-1515, 1985).

For metering reasons and reasons relating to simplified handling, theuse of phenothiazine solutions would be entirely desirable for the useof phenothiazine as a stabilizer in the distillation of ethylenicallyunsaturated carboxylic acids, such as, for example, acrylic acid, butthis is prevented by the poor solubility of phenothiazine inconventional solvents (in some cases substantially less than 10%), withthe result that correspondingly large storage apparatuses would berequired. The choice of solvents is furthermore limited by the fact thatthey have to be completely inert to acrylic acid and furthermore may notdistill over during the distillation, since otherwise the purity of theacrylic acid would not comply with the claims (acrylic acid is generallyused in polymerization processes which are sensitive to impurities).

With a few exceptions, for example the use of an approximately 6%strength solution of phenothiazine in ethyl acetate as a shortstopinhibitor for acrylic acid (this is to be understood as meaning the veryrapid metering of phenothiazine as an inhibitor for the polymerizationof ethylenically unsaturated carboxylic acids, for example in the caseof incipient polymerization of acrylic acid without additives or onoverheating of storage containers and because of polymerization as aresult of a runaway reaction), phenothiazine is therefore used in solidform in the industrial production of ethylenically unsaturatedcarboxylic acids.

A conventional form is the preparation and use of phenothiazine in theform of scales, liquid phenothiazine, for example after purification bydistillation is complete, being applied to a chilled roll and theresulting layer of solid phenothiazine being broken off the roll bymeans of a scraper system in the form of scales. The thickness of thescales can be controlled within certain limits; in general, scales orflakes having a thickness of from about 0.2 to 4 mm and measuring from0.2 to 20 mm in the other two dimensions can be prepared in this manner.During the preparation of the scales themselves or during the subsequenttransport in the production facility to storage means or later incorresponding transport containers to the consumer, fine dust having aparticle size of <300 μm is additionally formed in amounts of up to 5%and has to be substantially removed by classical methods (for examplesieving and recycling to the preparation process for phenothiazine). Alow fine dust content is necessary because fine phenothiazine dust has ahigh tendency to form explosive mixtures in air, which is thus relevantfor safety during handling of this substance.

From the description of the preparation process for solid phenothiazine,it is evident that the resulting solid particle conglomerate isinhomogeneous from the point of view that the particles have arelatively large variability of the particle size distribution withinsaid limits, which as such are to be understood merely by way ofexample. In addition, fine fractions may once again be formed duringtransport in the production facility or during transport to the consumeras a result of poor shear stability, which fine fractions, owing to thehigher dust explosion class (easier ignitability as a mixture with air,i.e. ignition at lower ignition energy which can be supplied by ignitingsparks as well as by static electricity or friction), for fine dust andthe higher risk of inhalation during handling of phenothiazine,necessitate increased safety and work safety precautions.

Furthermore, the dissolution behavior of phenothiazine in ethylenicallyunsaturated carboxylic acids is of course dependent on the particle sizedistribution. From the above, it follows that, depending on thetransport distance or different mechanical loads, different dissolutionrates are to be expected on reaching the user, which necessitates agreater monitoring effort and inclusion of time buffers duringoperation, for example in the dissolution process, and finally meansinsufficient process stability.

Improved and also better reproducible solubility behavior should beachieved by the preparation and use of phenothiazine of extremely smallparticle size, but this gives rise to the abovementioned safety problemsand accordingly safety precautions which additionally have to be takenin respect of dust explosively and problems relating to occupationalhygiene, as well as the fact that solids having a very small particlesize have only a low bulk density, which has adverse effects on theeconomics of transport. Furthermore, with the use of phenothiazine inthe form of scales and shipping in large containers, for example in bigbags having contents weighing up to 1 metric ton in practice, caking ofthe material is observed and the material then has to be brought into apourable and meterable form in a time-consuming and labor-intensivemanner by employing mechanical methods, such as vibration, braking orcomminution by means of rods.

The object was therefore to develop a preparation process forphenothiazine which does not have said disadvantages but givesphenothiazine having a narrower particle size distribution, a smallerfine particle fraction, constant and improved solution properties andhigh bulk density as well as improved transport properties compared withthe preparation process of the prior art and in addition is economicalwith respect to the preparation.

It has now surprisingly been found that the above object is achieved bya process for the preparation of phenothiazine granules having a narrowparticle size distribution, phenothiazine having a purity of at least98% in liquid form being forced through a means provided with holes andan oscillation of product-specific frequency, which supports theformation of uniform drops, being introduced into the liquid in asuitable manner. The phenothiazine emerging from the holes enters acooling medium having a temperature of from −196° C. to +120° C., theliquid phenothiazine drops produced being brought to a temperature belowthe melting point and said drops being, if required, further solidifiedin a downstream cooling zone.

The particle diameter can be controled by various parameters. Animportant parameter is the diameter of the holes in the perforatedplate.

According to the invention, a die plate having holes with a diameter inthe range of from 0.2 to 1.5 mm, preferably with a diameter in the rangefrom 0.3 to 0.9 mm, in particular with a diameter in the range of from0.4 mm to 0.6 mm, is suitable for forcing through the liquidphenothiazine.

Granulation apparatuses, as used, for example, for the preparation ofpolyethylene waxes, oxidized polyethylene, resins having a tow molecularweight, atactic polypropylene, fats or alcohols or wax mixtures, canalso be used for the preparation of the phenothiazine granulesdescribed.

In said granulation apparatuses, the phenothiazine to be granulated orto be pelleted, in liquid form, is forced through a perforated plate, afrequency being applied to the phenothiazine.

Usually, the resonant frequency to be applied is in the range of from100 to 10 000 Hz, preferably in the range of from 200 to 5 000 Hz. Theoptimum frequency for achieving a uniform drop spectrum can bedetermined in a simple manner by a person skilled in the art by means ofoptimization experiments.

The liquid droplets formed thus formed are solidified to sphericalellipsoidal solid particles in a cooled gas stream (cooling medium).After solidification, which may be accompanied by complete or partialcrystallization, which initially takes places in the outer region of theliquid droplets, complete solidification or crystallization is effectedin general by a downstream cooling zone.

The surface structure as well as the porosity of the solid particle ismoreover influenced by other parameters, such as, for example, thevelocity of the countercurrent cooling medium and the temperature of thecooling medium.

Suitable cooling media are air, nitrogen and inert gases having atemperature in the range of from −196 to +120° C., in particular havinga temperature in the range of from −40 to +100° C., preferably having atemperature in the range of from +20 to +100° C.

The velocity with which the cooling medium flows countercurrent to thephenothiazine drops is usually in the range of from 0.1 to 10 m/s,preferably in the range of from 0.5 to 5 m/s.

In a further embodiment, vaporizing nitrogen (T=>−196° C.) is used asthe cooling medium. With the use of vaporizing nitrogen as a coolingmedium, the height of the apparatus can be smaller than if, for example,air or an inert gas (e.g. nitrogen) at room temperature or in cooledform (from −10 to 20° C.) is used as the cooling medium.

The process according to the invention makes it possible to preparegranules having a particle size distribution in the range of 300-3 000μm, in particular having a particle size distribution in the range offrom 500 pm to 2 000 pm. The volume fraction of the particles havingthis particle size distribution is, according to the invention, at least90%, in particular >95%, based on the total volume.

The fine particle fraction, i.e. particles having a size of <300 μm, is<3% by weight, based on the total mass, in general even less than 2% byweight, based on the total mass of granules. The fine particle fractionsformed and also any resulting coarse particle fractions can be separatedoff by simple methods known to a person skilled in the art, for exampleby sieving methods.

The phenothiazine granules prepared by the process according to theinvention have a smaller fine particle fraction and substantiallyimproved solubility properties compared with phenothiazine scalesprepared by the known processes or pellet material.

Furthermore, it was possible to show that the granules preparedaccording to the invention have better shear stability, i.e. exhibitless abrasion under mechanical stress than the abovementioned knownproducts.

Thus, it was surprisingly found that, with the use of cooled air orcooled inert gas in the temperature range of from −10 to 20° C., incontrast to vaporizing nitrogen as a cooling medium, granules having ahigher bulk density and further improved shear stability, i.e. betterabrasion behavior, could be obtained in the preparation according to theinvention.

The bulk densities of the granules obtained by the process according tothe invention are preferably in the range of from 720 to 780 kg/m³.

The granules prepared according to the invention furthermore have asubstantially narrower particle size distribution. The effect ofabrasion owing to a shear stress is substantially smaller in the case ofthe phenothiazine granules according to the invention than in the caseof the phenothiazine scales prepared by the known process or pellets(cf. example 3).

The solubility behavior of the phenothiazine granules prepared can beinfluenced, for example, by varying the temperature of the coolingmedium used. Thus, the solubility of the phenothiazine granules inacrylic acid can be substantially improved if the cooling medium has atemperature in the range of from −10 to +80° C., preferably from 0 to+60° C., during the preparation, i.e. on contact with, or on meeting,the liquid phenothiazine. The use of vaporizing nitrogen as a coolingmedium results in a solubility which is lower but nevertheless highercompared with phenothiazine scales (cf. example 2).

The dissolution rate up to reaching a concentration of 1.5% in acrylicacid is in the range of from 5 to 14 minutes, in particular in the rangeof from 7 to 10 minutes, at room temperature in the case of granulesaccording to the invention which have a particle size fraction of from 1000 to 1 400 μm.

The phenothiazine granules prepared according to the invention aresuitable, particularly because of their narrow particle sizedistribution, as additives in oils and lubricants, as a polymerizationinhibitor or stabilizer or as pesticides in agriculture.

EXAMPLES

Method for determining the solubility behavior of solid phenothiazine ofdifferent forms and particle size distributions

The solubility behavior is determined in comparative experiments byadding from 2 to 3% by weight, based on the total mass, of phenothiazineat room temperature to commercially available acrylic acid (Aldrich,stabilized with hydroquinone monomethyl ether). The maximum solubilityof phenothiazine in acrylic acid at room temperature is about 2.8% (Wm).Thereafter, at time intervals of from 1 to 5 mm, either a.) a sample ofthe dispersion was taken and filtered and the phenothiazine content wasdetermined by UV spectroscopy or b.) the phenothiazine content wasdetermined directly by means of an NIR probe which dipped into thedispersion of phenothiazine in acrylic acid (NIRVIS universalspectrometer from Büchi having a transmission probe with 1.5 mm slitwidth. In order to prevent disturbances by solid particles in themeasuring slit, this was closed by means of a metal screen having a meshsize of 0.18 mm).

Example 1

Determination of the Solubility Behavior of Phenothiazine Pellets,Scales and Granules

According to method 1 b, the solubility behavior of phenothiazinepellets (hemispheres or hemiellipsoids having a base diameter of 4-6 mmand a height of about 2-3 mm), scales (for description, see text above)and two granules prepared in different ways (granules 1, cooling mediumliquid or vaporizing nitrogen; granules 2, cooling medium air or inertgas (from −10 to +20° C.)) was compared. For this purpose, in each case1.33 g of the respective sample were added to 66 g of acrylic acid andmeasurements were carried out at intervals of one minute (Graph. 1).

From the solubility curves in FIG. 1, it is evident that granules 2(cooling medium, air, temperature about 20° C.) go into solutionssubstantially more rapidly than scales or granules 1 (cooling mediumvaporizing nitrogen) [for reasons of clarity, error bars were shown onlyin the case of granules 2].

Example 2

Comparison of the Solubility Behavior of Granules of Different SieveFractions and Different Methods of Preparation

In order to exclude the possibilities that the observed differencesbetween the granules prepared by using cooling medium close to roomtemperature and the granules prepared by using vaporizing nitrogen ascooling medium might be due to differences in the particle sizedistributions, two different sieve fractions (1 000-1 400 pm and1000-1700 pm) of granules 1 and granules 2 were prepared and thesolubility properties of these 4 samples were determined using method1b.

The Results Obtained are Shown in FIG. 2:

It is clear that, in the case of both sieve fractions, but especially inthe case of the sieve fraction having the particle size distribution inthe range of 1 000-1 400 pm, granules 2 go into solutions substantiallymore rapidly than granules 1. The graph shows that the dissolution ratein the case of the particle size fraction 1 000-1 400 pm up to reachinga concentration of 1.5% is virtually twice as fast at about 7 min forgranules 2 compared with about 14 min for granules 1, which constitutesa substantial application advantage in practice.

Example 3

Comparative Investigation of the Abrasion Behavior of DifferentPhenothiazine Particles

As a measure of the shear stability of different phenothiazine samplesand for simulating the abrasion behavior under transport conditions,samples were subjected to a shear stress in a shear cell of a rotationalshear vessel for a period of 30 min at a direct stress of 15 kPa. Thecomparison of the particle size distributions before and after themeasurement provides information about the abrasion behavior of theparticles.

The particle size distributions are shown in the diagrams below. Thecumulative undersize is shown along the ordinate and the particle sizealong the abscissa (logarithmic scale).

In FIG. 3 (phenothiazine scales), the solid squares represent the volumefraction of the particles up to the stated particle sizes, the plotbeing a cumulative plot. The particle size distribution was determinedagain according to the stated shear stress. That the particles aresmaller throughout on average is evident from the shift of the curve tothe left, toward smaller particle sizes. The graph also reveals thebroad particle size distribution, which ranges from particles <200 pm toparticles >4000 pm (in the unsheared state).

In comparison, the granules 1 and 2 (FIG. 4 and FIG. 5) have asubstantially narrower particle size distribution. In the case ofgranules 1, finer particles were likewise formed as a result of shearstress but the effect is substantially less pronounced than in the caseof the scales (smaller “hysteresis”). In the case of granules 2, theeffect is once again less pronounced: here, virtually no effect of theshearing on the particle size distribution and hence on the abrasion isobservable.

Comparison of the Bulk Densities of Granules 1 and 2

The bulk densities were determined using one sample each of granules 1and granules 2, which are characterized by the particle sizedistributions shown below, the bulk densities being significantly higherin the case of granules 2 at 760 kg/m³ than in the case of granules 1 at727 kg/m³: Particle size Granules 1 Granules 2 3150-4000 μm 0.1 <0.12000-3150 μm 0.6 0.1 1000-2000 μm 68.8 33.6 500-1000 μm 28.1 65.4250-500 μm 2.1 0.9 <250 μm 0.3 <0.1 <100 μm 0.1 <0.1 <75 μm 0.1 <0.1Bulk density 727 kg/m³ 760 kg/m³

1. A process for the preparation of phenothiazine granules having anarrow particle size distribution, phenothiazine having a purity of atleast 98% in liquid form being forced through a means provided withholes and a frequency being applied to the liquid phenothiazine and theliquid phenothiazine emerging through the holes entering a coolingmedium having a temperature in the range of from −196 to +120° C. sothat the liquid phenothiazine drops thus produced are brought to atemperature below the melting point and said drops are, if required,further solidified in a downstream cooling zone.
 2. The process asclaimed in claim 1, wherein the means provided with holes is a dieplate.
 3. The process as claimed in at least one of the precedingclaims, wherein the cooling medium has a temperature in the range offrom −40 to +100° C.
 4. The process as claimed in at least one of thepreceding claims, wherein the cooling medium used is nitrogen or air. 5.The process as claimed in at least one of the preceding claims, whereinthe cooling medium used is cooled air or cooled inert gas having atemperature in the range of from −40 to +100° C.
 6. The process asclaimed in at least one of the preceding claims, wherein thephenothiazine granules prepared have a particle size distribution in therange of from 300 to 3 000 μm, the volume fraction thereof being atleast 90%, based on the total volume.
 7. The process as claimed in atleast one of the preceding claims, wherein the fine particle fractionhaving particles of <300 μm is less than 3%, in particular less than 2%.8. The process as claimed in at least one of the preceding claims,wherein any fine particle fractions or coarse particle fractions formedare removed by suitable methods.
 9. The process as claimed in at leastone of the preceding claims, wherein the bulk density of thephenothiazine granules obtained is in the range of from 720 to 780kg/m³.
 10. The process as claimed in at least one of the precedingclaims, wherein the dissolution rate, in acrylic acid, of phenothiazinegranules having a particle size fraction in the range of from 1 000 to 1400 μm up to reaching a concentration of 1.5% is from 5 to 14 minutes.11. Phenothiazine granules having a narrow particle size distribution,obtainable by a process of one or more of claims 1 to
 10. 12. The use ofphenothiazine granules having a narrow particle size distribution asclaimed in claim 11 as additives in oils and lubricants, as apolymerization inhibitor or stabilizer or as pesticides in agriculture.